Ataxia-telangiectasia (A-T) is an autosomal recessive disorder associated with high incidence of lymphoid malignancies, neurological degeneration, immunodeficiency, radiation sensitivity and genetic instability (Meyn, Clin Genet, 1999, 55:289-304). Approximately 30-40% of all A-T patients develop neoplasia during their life (Peterson et al., 1992, Leukemia 6 Suppl. 1:8-13): more than 40% of all tumors are non-Hodgkin's B cell lymphomas, about 20% acute lymphocytic leukemias, and 5% Hodgkin's lymphomas (Morrell et al., 1986, J Natl Cancer Inst, 77:89-92; Hecht and Hecht, 1990, Cancer Genet Cytogenet, 46:9-19; Taylor et al., 1996, Blood 87:423-438; Sandoval and Swift, 1998, Med Pediatr Oncol 31:491-97). Lymphoid malignancies are of both B and T cell origin. T cell tumors comprise T cell lymphoma, T acute lymphocytic leukemia and T prolymphocytic leukemia. A-T patients suffer from increased mortality due to malignancy, infections of the respiratory system and various rare complications (Boder et al., 1975, Birth Defects Orig Artic Ser 11(1):255-70; Crawford et al., 2006, Arch Dis Child 91(7):610-611; Gatti et al., 2001, Clin Rev Allergy Immunol 20(1):87-108). Currently, there is no therapy available to prevent cancer or progressive neurodegeneration.
A-T is caused by biallelic mutations in the ATM gene. Over 600 different ATM mutations have been described (LOVD—Leiden Open Variation Database; Curator: Patrick Concannon). The ATM gene encodes a ˜350 kDa protein, phosphatidylinositol-3-like kinase, which is expressed abundantly in multiple tissues (Savitsky et al., 1995, Science 268:1749-1753; Chen and Lee, 1996, J Biol Chem 271:33693-33697; Uziel et al., 1996, Genomics 33:317-320) and plays an important role in cell cycle checkpoint control as well as repair responses to DNA double strand breaks (DSBs) (Jeggo et al., 1998, Trends Genet 14:312-316; Rotman and Shiloh, 1998, Hum Mol Genet 7:1555-1563; Barzilai et al., 2002, DNA Repair (Amst) 1:3-25). Absence of functional ATM protein results in chromosomal breakage and rearrangements, aberrant V(D)J recombination, and heightened sensitivity to radiation and chemicals with radiomimetic and prooxidant activity.
Although investigations into A-T have been greatly enhanced by the development of mouse models, disease penetrance in genetically identical mouse colonies at different laboratories can vary widely. Some ATM-deficient (Atm−/−) mice develop early lymphomas and have short life spans (2-5 months) (Barlow et al., 1996, Cell, 86:159-171; Elson et al., 1996, Proc Natl Acad Sci USA 106:1027-1032; Xu et al., 1996a, Genes Dev 10:2411-2422; Xu et al., 1996b, Genes Dev 10:2401-2410) while others display dramatically delayed phenotypes, where 50% of the mice remain viable after 7-12 months (Borghesani et al., 2000, Proc Natl Acad Sci USA 97:3336-3341; Petiniot et al., 2002, Mol Cell Biol 22:3174-3177; Schubert et al., 2004, Hum Mol Genet 13:1793-802; Reliene and Schiestl, 2006a, DNA Repair (Amst) 5:852-959. Lifespan studies on inbred and mixed background mice have failed to show phenotypic differences (Reliene and Schiestl, 2006b, DNA Repair (Amst) 5:651-653), suggesting other factors besides genetic diversity are contributing to disease penetrance. Environmental factors such as housing conditions and diet have been postulated to be contributing factors (Rao and Crockett, 2003, Toxicol Pathol 31:243-250). Herein, Applicants examined another potential contributor—the intestinal microbiota.
Intestinal bacteria have been implicated in several types of cancer. In animal models of colorectal cancer, lower incidences in germ-free animals point toward intestinal microbes playing a causative role (Rescigno, 2008, Curr Drug Targets 9:395-403; Rowland, 2009, Curr Pharm Des 15:1524-1527). Helicobacter species have been associated with enhanced carcinogenesis including liver cancer, colon cancer, and mammary carcinoma (Ward et al., 1994a, Am J Pathol 145:959-968; Ward et al., 1994b, J Natl Cancer Inst 86:1222-1227; Rao et al., 2006, Cancer Res 66:7395-7400). Conversely, probiotic formulations containing lactic acid bacteria have been shown to reduce the incidence of chemically mediated hepatocellular carcinoma and colon cancer in rats (Pool-Zobel et al., 1996, Nutr Cancer 26:365-380; Kumar et al., 2011, Gene 490:54-59).
According to the latest statistics reported by the American Cancer Society, the most common type of cancer currently is lung cancer, with more than 222,000 new cases expected in the United States in 2010. Prostate cancer follows with 217,730, breast cancer with 209,060, and colorectal with 142,570 new cases expected in 2010 (American Cancer Society, Cancer Facts and Figures 2010, 2010). It is estimated that half of all cancer patients will receive radiotherapy during the course of their treatment for cancer (Weiss and Landauer, 2003, Toxicology 189(1-2):1-20). Of those cancer patients who are cured it is estimated that 49% are cured by surgery, 40% by radiotherapy (RT) alone or combined with other treatments and 11% by chemotherapy alone or combined with other treatments (Levitt and Leer, 1996, Acta Oncol 35(8):965-6). Even in advanced or recurrent cases, radiotherapy is a highly effective option for temporary relief and control of symptoms (Levitt and Leer, 1996, Acta Oncol 35(8):965-6; Hoskin et al., 2001, Clin Oncol (R Coll Radiol) 13(2):88-90).
Radiotherapy is commonly used as a component of therapy for a wide range of malignant conditions. About half of all cancer patients receive radiation therapy as either curative or palliative treatments (American Cancer Society, Cancer Facts and Figures 2010, 2010). Radiotherapy is frequently used to achieve local or regional control of malignancies either alone or in combination with other treatments such as chemotherapy or surgery. Irradiation of noncancerous “normal” tissues during the course of therapeutic radiation can result in a range of side effects including self-limited acute toxicities, mild chronic symptoms, or severe organ dysfunction. The likelihood of developing these complications relates to the volume of an organ irradiated, the radiation dose delivered, fractionation of the delivered dose, the delivery of radiation modifiers, and individual radiosensitivity (Barnett et al., 2009, Nat Rev Cancer 9(2):134-42). Efforts to reduce the toxicities associated with therapeutic radiation have centered on both technological improvements in radiation delivery and chemical modifiers of radiation injury. Normal tissue toxicity remains a limiting factor in the treatment of many diseases with radiation therapy.
Tissue toxicity may range from no symptoms, to changes in tissue structure and function, and all the way to severe cosmetic and life-altering changes in organ function (Lee et al., 2009, Int J Radiat Oncol Biol Phys 73(4):1121-8). The effects of radiotherapy on normal tissue could be divided into early (acute) reactions, which occur within 90 days of radiotherapy, and late reactions that occur more than 90 days after radiotherapy, with a potential to continue for life span (Kirkpatrick et al., Int J Radiat Oncol Biol Phys 76(3 Suppl):S42-9). Early reactions principally affect high turn-over tissues, such as skin, the gastrointestinal tract and bone marrow where the onset and severity of the reactions reflect the balance between the rate of stem/progenitor-cell killing and the rate of regeneration of surviving cells (Van der Kogel, 1993; Kirkpatrick et al., Int J Radiat Oncol Biol Phys 76(3 Suppl):S42-9). Severe acute reactions are rare and usually are associated with DNA DSB repair deficiency syndromes such as Ataxia Telangiectasia (ATM) and Nijmegen Breakage Syndrome (NBS).
Thus, there is a long felt need in the art for providing methods and compositions useful for the treatment, prevention and delaying onset of AT-associated conditions and cancer as well as radiation-induced toxicity to normal tissue during and/or caused by radiation treatment. The present invention described herein, provides such compositions and methods.